Abstract Plasmacytoid dendritic cells (pDC) are an important component of the innate immune response, contributing to the immune control of viral infections by producing large amounts of anti-viral type I interferon and modulating adaptive responses. Our laboratory has elucidated many of the key pathways in human pDC activation and maturation, especially with regard to ssRNA viruses such as HIV-1 and influenza virus. We demonstrated for the first time that pDC sense HIV-1 associated single stranded RNA through Toll-like receptor (TLR) 7, a process that requires CD4-dependent internalization into endosomal compartments where downstream IFN signaling is activated via interferon regulatory factor 7 (IRF). Despite triggering the same TLR (TLR7), HIV-1 and influenza differentially impact pDC. HIV-1 induces large amounts of type I IFN but fails to fully mature pDC into antigen presenting cells or APC (?IFN? phenotype vs ?APC? phenotype), whereas influenza induces both phenotypes. Notably, we also show that HIV-2 activates pDC to become APC, similar to influenza. HIV-2 is a naturally attenuated form of HIV, which results often in control of the virus and delayed disease development. We have now identified a set of long noncoding RNAs (lncRNAs) that can modulate both human conventional DC (cDC) and pDC function, including their IFN and maturation/APC phenotypes. We have also described sets of IFN-inducible lncRNAs in human pDC as well as pDC-unique lncRNAs that could potentially impact pDC function in response to virus sensing. The overall goal of this application is to investigate the role of virus induced-lncRNA in pDC regulation, given that viruses can induce lncRNAs, lncRNAs are important regulators of the expression and function of genes and their encoded proteins, and that lncRNAS affect immune cell behavior, including that of dendritic cells. We hypothesize that ssRNA viruses (HIV-1, influenza, HIV-2) can impact pDC function through their differential induction of regulatory lnc-RNAs. The specific aims are to: (1) Apply RNA sequencing to identify unique virus-induced lncRNA in human pDC; (2) Functionally define lncRNA that modulate the IFN response in pDC, and (3) Mechanistically distinguish lncRNA that segregate pDC responses to HIV-1 and HIV-2. Our current knowledge about the identity and function of lncRNAs in infected innate immune cells is very limited, especially for human innate immune cells. Identifying virus inducible lncRNAs may lead to the discovery of novel cellular pathways to aid the development of therapeutic tools for the treatment and eradication of HIV-1 infection.